Low-dose hydrocortisone infusion attenuates the systemic inflammatory response syndrome

There is increasing evidence that the hypercortisolemia in inflammatory diseases suppresses the elaboration of proinflammatory cytokines, thus protecting the host from its own defence reactions. In severe sepsis and septic shock cortisol levels are usually elevated, but some patients may have relative adrenal insufficiency. This may contribute to the overwhelming systemic inflammatory response syndrome. We evaluated the impact of low-dose hydrocortisone infusion (10 mg/h) on the course of the systemic inflammatory response syndrome. This dose corresponds to a maximum secretory rate of cortisol achieved in corticotropin-stimulated healthy humans. In a prospective observational study 57 surgical patients with severe sepsis or septic shock were studied, of which in addition to the conventional treatment 12 patients were infused with low-dose hydrocortisone, and 45 were treated without any corticosteroid. In the longitudinal analysis the systemic inflammatory response — as judged by body temperature, cardiovascular response, and kinetics of inflammatory mediators such as phospholipase A₂, C-reactive protein, and neutrophil elastase — started to differ in favor of the hydrocortisone-treated patients after 2 days of treatment (P < 0.05, Mann-Whitney U test). The difference disappeared after withdrawal of exogenous cortisol. Shock reversal was achieved in all patients treated with low-dose hydrocortisone. The data provide evidence that low-dose hydrocortisone infusion attenuates the systemic inflammatory response in human septic shock. From an immunological point of view a relative cortisol deficiency may contribute to the amplified immune response in systemic inflammatory diseases. A randomized clinical trial must clarify the impact of low-dose hydrocortisone infusion on the clinical course and outcome of septic shock patients.Abbreviations TNF Tumor necrosis factor - PLA₂ phospholipase A₂ - CRP C-reactive protein - E-PI neutrophil elastase-₁-proteinase inhibitor complex - IL interleukin Correspondence to: J. Briegel     

大肠杆菌DNA诱导全身性炎症反应综合征的作用机制研究

目的: 探讨细菌DNA是否参与全身性炎症反应综合征(SIRS)的发生及其可能机制。方法: 碱裂解法抽提纯化大肠杆菌DNA(EC DNA); 观察EC DNA攻击小鼠的死亡率及大鼠血清TNF-α、IL-6的变化情况; 体外培养小鼠单核细胞株ANA-1细胞, 采用不同终浓度的EC DNA、LPS刺激ANA-1细胞,测定细胞培养上清中TNF-α、IL-6的释放情况, 并检测人单核细胞株THP-1细胞表面Toll样受体9(TLR9)和Toll样受体4(TLR4)表达以及核转录因子κB(NFκB)的活化情况。结果: EC DNA可导致小鼠死亡, 并具有明显的量效关系, 小牛胸腺DNA和DNA酶消化的EC DNA则不能引起小鼠死亡; EC DNA与LPS均可导致大鼠血清TNF-α、IL-6水平升高,变化趋势相似, 但EC DNA所致的TNF-α峰值早于LPS组1 h出现。在体外实验中, 不同浓度的EC DNA、LPS可诱导ANA-1细胞大量释放TNF-α、IL-6, 以及THP-1细胞表面TLR9和TLR4的高表达, 但EC DNA诱导NFκB活化的能力远小于LPS。结论: EC DNA可以和LPS一起参与SIRS的发生, 可能机制与诱导单核细胞TNF-α、IL-6的释放有关, 但EC DNA诱导细胞因子释放的信号转导过程中可能尚有其它途径的存在。     

全身炎性反应综合征中性粒细胞线粒体细胞色素c的研究进展

全身炎性反应综合征(systemic inflammation response syndrome,SIRS)是多种疾病发展至多器官功能障碍综合征(multiple organs dysfunction syndrome,MODS)的前期表现.中性粒细胞,又名多形核白细胞(polymorphonuclear neutrophil,PMN)是重要的炎症效应细胞,其凋亡延迟或障碍进而导致炎症反应持续发展和加剧是SIRS的主要病理生理过程.线粒体细胞色素c(cytochrome c,Cyt-c)是重要的凋亡蛋白,通过内源性和外源性等多种凋亡途径参与PMN凋亡.深入探讨SIRS时PMN凋亡异常的分子机制,研究线粒体Cyt-c在PMN凋亡中的作用,寻找诱导PMN适时、适度凋亡的有效方法,对于限制组织损伤、控制炎症反应、减轻SIRS有重要意义.     

创伤性全身炎症反应综合征大鼠动物模型的建立

目的　探讨建立可重复的大鼠创伤性全身炎症反应综合征实验模型。 方法　Wistar大鼠30 只大鼠随机分为对照组（A组）,脂多糖组（B组）和实验组（C组）。B组在完成股动脉、股静脉插管后注入脂多糖（LPS,12 mg/kg）,C组采取手术切除1/3肝脏及锤击右侧股骨3次的方法,而A组在同等条件下不进行有创实验。2 h后采血测定血清中丙氨酸氨基转移酶(ALT) 、天冬氨酸氨基转移酶(AST) 、尿素氮(UN) 和肌酐(Cr) 的含量,12 h 后处死大鼠, 取大鼠肺及肝脏组织做病理切片并HE染色。 结果　B组及C组大鼠在建模后血清AL T、AST、UN 和Cr 含量明显增高,与A组比较差异有统计学意义( P<0.01);C组大鼠血清UN ,Cr 含量较B组增高,差异有统计学意义( P<0.05)。光镜观察发现B组及C组大鼠的肝脏和肺脏有组织损伤及明显的炎性反应;B组及C组其肝脏及肺的病理变化差别不明显。 结论　此方法可较方便的制作大鼠创伤性全身炎症反应综合征动物模型。     

Meconium aspiration syndrome induces complement-associated systemic inflammatory response in newborn piglets

The pathophysiology of meconium aspiration syndrome (MAS) is complex. We recently showed that meconium is a potent activator of complement. In the present study, we investigated whether the complement activation occurring in experimental MAS is associated with a systemic inflammatory response as judged by granulocyte activation and cytokine and chemokine release. MAS was induced by the instillation of meconium into the lungs of newborn piglets (n = 8). Control animals (n = 5) received saline under otherwise identical conditions. Haemodynamic and lung dynamic data were recorded. Complement activation, revealed by the terminal sC5b-9 complex (TCC), and cytokines [interleukin (IL)-6 and IL-8] were measured in plasma samples by enzyme immunoassays. The expression of CD18, CD11b and oxidative burst in granulocytes was measured in whole blood by flow cytometry. Plasma TCC increased rapidly in the MAS animals in contrast with controls (P < 0.0005). The TCC concentration correlated closely with oxygenation index (r = 0.48, P < 0.0005) and ventilation index (r = 0.57, P < 0.0005) and inversely with lung compliance (r = -0.63, P < 0.0005). IL-6 and IL-8 increased in MAS animals compared with the controls (P = 0.002 and P < 0.001, respectively). Granulocyte oxidative burst declined significantly in the MAS animals compared with the controls (P < 0.02). TCC correlated significantly with IL-6 (r = 0.64, P < 0.0005) and IL-8 (r = 0.32; P = 0.03) and inversely with oxidative burst (r = -0.37; P = 0.02). A systemic inflammatory response associated with complement activation is seen in experimental MAS. This reaction may contribute to the pathogenesis of MAS.     

Circulating complement proteins in patients with sepsis or systemic inflammatory response syndrome.

The systemic inflammatory response of the body to invading microorganisms, termed sepsis, leads to profound activation of the complement system. Pathophysiological concepts suggest that complement activation occurs very early in this syndrome. Thus, we discuss whether the determination of concentrations of the complement components C3a, C5a, and C3 in plasma as well as of the C3a/C3 ratio might be helpful to diagnose sepsis early. For this purpose, 33 patients from an intensive care unit were monitored for 10 days. In comparison with healthy donors, C3a levels and the C3a/C3 ratio of intensive-care-unit patients were significantly elevated (P < 0.0001) on admission. In contrast, C3 levels were significantly reduced (P < 0.0001) but increased during the study. C5a levels in the plasma of healthy donors and patients were identical. Twenty-two of 33 patients fulfilled microbiological and clinical criteria of sepsis. Eleven patients had signs of systemic inflammatory response syndrome but no microbiological evidence of sepsis. The groups could be differentiated from each other by their C3a levels or their C3a/C3 ratios during the first 24 h after the clinical onset of sepsis (P < 0.05). Septic patients in shock had higher C3a levels than normotensive septic patients, although the differences were not significant. Nonsurvivors had significantly higher C3a levels on admission than survivors (P = 0.0185). No differences were found between septic patients who developed adult respiratory distress syndrome and those who did not. Thus, determination of C3a concentrations in plasma may prove useful (i) to diagnose sepsis early, (ii) to differentiate between patients with sepsis and those with systemic inflammatory response syndrome, and (iii) to assess prognosis.     

Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation

Interleukin-1β (IL-1β) is a potent inflammatory cytokine that is usually cleaved and activated by inflammasome-associated caspase-1. To determine whether IL-1β activation is regulated by inhibitor of apoptosis (IAP) proteins, we treated macrophages with an IAP-antagonist "Smac mimetic" compound or genetically deleted the genes that encode the three IAP family members cIAP1, cIAP2, and XIAP. After Toll-like receptor priming, IAP inhibition triggered cleavage of IL-1β that was mediated not only by the NLRP3-caspase-1 inflammasome, but also by caspase-8 in a caspase-1-independent manner. In the absence of IAPs, rapid and full generation of active IL-1β by the NLRP3-caspase-1 inflammasome, or by caspase-8, required the kinase RIP3 and reactive oxygen species production. These results demonstrate that activation of the cell death-inducing ripoptosome platform and RIP3 can generate bioactive IL-1β and implicate them as additional targets for the treatment of pathological IL-1-driven inflammatory responses.     

CCL2 as a trigger of manifestations of compensatory anti-inflammatory response syndrome in mice with severe systemic inflammatory response syndrome

Patients with compensatory anti-inflammatory response syndrome (CARS) are at a higher risk for infection with various opportunistic pathogens. CARS develops commonly in association with the manifestation of systemic inflammatory response syndrome (SIRS). In the present study, the role of SIRS-associated soluble factors on the CARS development was examined in mice with pancreatitis, a carrier of typical SIRS. Following the production of SIRS-related cytokines [tumor necrosis factor alpha and interleukin (IL)-1beta], CC chemokine ligand 2 (CCL2), IL-4, and IL-10 (typical CARS cytokines) were detected in the sera of mice with pancreatitis. CCL2 has been described as an essential chemokine for the T helper cell type 2 manifestation. CARS effector cells (cells with an ability to produce IL-4 and IL-10) were not generated from normal T cells after stimulation with SIRS-related cytokines. However, these cells were generated from normal T cells after cultivation with peripheral blood neutrophils (PMN) from SIRS mice in a dual-chamber transwell. Normal T cells did not convert to CARS effector cells after transwell cultures with PMN from normal mice. CCL2 was detected in culture fluids of PMN from SIRS mice, and PMN from normal mice did not produce CCL2 into their culture fluids. CARS effector cells did not appear in PMN-depleted SIRS mice or SIRS mice treated with anti-CCL2 monoclonal antibody, and these cells were demonstrated in PMN-depleted SIRS mice after treatment with recombinant murine CCL2. These results indicate that CCL2 produced by PMN from SIRS mice is an active molecule on the SIRS-associated CARS manifestation.     

Direct hemoperfusion by using Lixelle column for the treatment of systemic inflammatory response syndrome

We have previously reported that Lixelle which was used for beta2-microglobulin (BMG) adsorption column could adsorb not only BMG but also inflammatory cytokines and microbial fragments such as endotoxin (ET) and peptidoglycan (PG). The aim of this study was to estimate that an adsorbent column was used in direct hemoperfusion in patients clinically having systemic inflammatory response syndrome (SIRS), and the relationship between a decrease in cytokines and clinical course was examined. Meanwhile, as regards in vivo rate of removing cytokine based on pre-treatment cytokine concentration versus pre-column concentration at the time of evaluation, it increased with lapse of time, and the removing rate was 40% with 4 h direct hemoperfusion by using the Lixelle column in some of the patients. As to in vivo rates of adsorbing IL-1beta, IL-1Ra, IL-6, IL-8 and TNF-alpha before and after the use of column at the time of evaluation, the rates 5 min after the start were 31.4, 39.3, 36.4, 76.2 and 71.6% respectively. Clinically, it was possible to increase blood pressure and recover from shock status. With the use of this column, removal of inflammatory cytokine by adsorption can be expected. Thus, it can be applied to the treatment of hypercytokinemia.     

谷氨酰胺强化的肠外营养对普外科全身炎症反应综合征的影响

目的: 研究谷氨酰胺(Gln)增强的肠外营养对普外科全身炎症反应综合征(SIRS)的影响。方法: 将40例符合SIRS诊断标准的外科危重和大手术后病人随机分成Gln组和对照组, 各20例, 两组均给予常规外科治疗, 并于术后第1-3 d开始肠外营养连续7 d, 其中Gln组的氮量由20% L-丙氨酰-L-谷氨酰胺溶液供给(0.5 g·kg^-1·d^-1), 其余部分供给(7-11.4)%氨基酸溶液, 对照组的氮量仅用(7-11.4)%氨基酸溶液供给。两组病人分别于肠外营养前和营养后7 d抽取外周血测量血红蛋白(Hb)、白蛋白(Alb)、转铁蛋白(TRF)、免疫球蛋白G(IgG)、免疫球蛋白A(IgA)、免疫球蛋白M(IgM)水平, 并进行APACHEⅡ评分。结果: Gln组经肠外营养治疗后IgG水平、TRF水平分别由(9.2±3.1) g/L、(1.17±0.3) g/L增高至(14±2.8) g/L、(1.36±0.7) g/L, 相比差异显著(P<0.05)。治疗后两组APACHEⅡ评分均低于治疗前(P<0.05), Gln组评分又低于对照组(P<0.05)。结论: Gln增强的肠外营养能促进普外科SIRS病人蛋白质合成代谢, 提高机体免疫功能, 减轻病情的危重程度。     

Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer

We report the death of an 18-year-old male with partial ornithine transcarbamylase (OTC) deficiency who participated in a pilot (safety) study of gene therapy. The vector used for this trial was based on human adenovirus type 5, deleted in E1 and E4, and contained human OTC cDNA. It was infused into the right hepatic artery at a dose of 6x10(11)particles/kg. Approximately 18 h. following gene transfer the subject was noted to have altered mental status and jaundice--clinical signs not seen in any of the first 17 subjects in this study. Subsequently, his clinical course was marked by systemic inflammatory response syndrome, biochemically detectable disseminated intravascular coagulation, and multiple organ system failure, leading to death 98 h following gene transfer. Post-mortem examination was consistent with the clinical course, and vector DNA sequences were readily detectable in most tissues. The subject had high serum levels of IL-6 and IL-10 but normal TNFalpha immediately after infusion of the vector. This experience points to the limitations of animal studies in predicting human responses, the steep toxicity curve for replication defective adenovirus vectors, substantial subject-to-subject variation in host responses to systemically administered vectors, and the need for further study of the immune response to these vectors.     

新生儿全身炎症反应综合征时TREM-1表达的实验研究

目的探讨新生儿全身炎症反应综合征（SIRS）时,髓系细胞触发受体1（Triggering Receptor Expressed on Myeloid cells-1,TREM-1）在外周血单核细胞核酸和蛋白质水平的表达及其意义。方法实验对象分为正常对照组,SIRS组,严重SIRS组,SIRS伴休克组。实验组病例确诊后各抽取外周血5ml,按照Dapino P的方法分离单核细胞。四组分别提取RNA及总蛋白。用逆转录聚合酶链反应（RT—PCR）检测TREM-1 mRNA的表达,用Western Blot方法检测TREM-1蛋白的表达。结果各组Trem-1 mRNA／β-actin及TREM-1蛋白／GAPDH比值依次增加,组间差异有统计学意义（P〈0．01）。结论新生儿全身炎症反应综合征时TREM-1的表达有明显变化,并随着病情分级严重程度而表达上调。     

Urocortin and adrenomedullin prevent lethal endotoxemia by down-regulating the inflammatory response

Urocortin 1 (UCN) and adrenomedullin (AM) are two neuropeptides that have emerged as potential endogenous anti-inflammatory factors based on their production by and binding to immune cells. Because human septic shock involves excessive inflammatory cytokine production, we investigated the effect of UCN and AM in the production of inflammatory mediators and their therapeutic actions in two models of septic shock. Both peptides down-regulated the production of inflammatory mediators by endotoxin-activated macrophages. The administration of UCN or AM protected against lethality after cecal ligation and puncture or after injection of bacterial endotoxin and prevented septic shock-associated histopathology, such as infiltration of inflammatory cells and intravascularly disseminated coagulation in various target organs. The therapeutic effect of UCN and AM was mediated by decreasing the local and systemic levels of a wide spectrum of inflammatory mediators, including cytokines, chemokines, and the acute phase protein serum amyloid A. Importantly, UCN or AM treatment was therapeutically effective in established endotoxemia. In conclusion, UCN and AM could represent two multistep therapeutic agents for human septic shock to be used in combination with other immunomodulatory agents or complementary as anti-inflammatory factors to other therapies.     

新生儿全身炎症反应综合征与IL-10基因多态性的相关性研究

目的探讨IL-10基因启动子区1082位点基因型及等位基因与新生儿全身炎症反应综合征(SIRS)的关系。方法采用ELISA法检测血清IL-10水平及限制片断长度多态分析-聚合酶链反应方法(RFLP/PCR)对54例全身炎症反应综合征新生儿和40例随机挑选健康体检的新生儿的IL-10的基因启动子区1082位点等位基因进行分析,计算该位点的基因分布频率和相对危险度OR值;并进行卡方检验,筛选有意义基因型。结果(1)SIRS组血清IL-10水平显著升高,与对照组比较差异显著。(2)SIRS组患儿IL-10 1082位点GG型分布频率为61.1%,AA分布频率为5.6%,GA分布频率为33.3%,以上三个基因型在疾病组与正常组之间进行卡方检验,χ2值分别为7.53,1.30,6.00,GG型与正常对照组比较均有显著性差异(P<0.01)。AA型与正常对照组比较亦有显著性差异(P<0.05)。疾病组G等位基因的分布频率为77.8%;A等位基因的分布频率为22.2%;疾病组与正常组之间进行逐个基因型的比较,以相对危险度0R值计算,计算结果GG的0R值为3.26;AA的0R值为0.20;GA的0R值为0.61。结论IL-10的基因启动子区1082位点GG是中国北方汉族新生儿SIRS的易感基因;而AA为抗感基因。通过对IL-10基因启动子区1082位点的基因多态性的搜索,发现IL-10基因启动子区1082位点的基因型对新生儿SIRS的发生、发展、诊断、预后、预测有重要意义。     

Systemic inflammatory response syndrome: new concepts

Systemic inflammatory response syndrome is secondary to several insults whose purpose is to limit and reverse the injury. The outcome and intensity of the inflammatory response is determined by injury extension and balance between inflammatory and compensatory antiinflammatory responses. The interaction of the several soluble and cellular mediators of inflammatory and antiinflammatory responses determine the next evolutive phases: a) local inflammatory response; b) systemic inflammatory response; c) massive systemic inflammatory response; d) immunologic paralysis; and e) immune dissonance. If the last three phases do not control, cell damage can be amplified and thus perpetuating the infectious process and leading the patient to multiple organ dysfunction. Gamma interferon and steroids as modulators of the inflammatory response, in stages of paralysis and immune dissonance has been studied in clinical and experimental trials with promising results, but more studies to are needed validate their usefulness.     

核转录因子κB在全身为症反应综合征中的作用

核转录因子κB（NF－κB）是一种多向性核转录调工蛋白,参与多种炎症介质基因的转录和调控,在炎症、免疫反应中发挥重要作用。本文就NF－κB与全身炎症反应综合征的关系以及阻断NF－κB对全身炎症反应综合征、多器官功能不全综合征的治疗作用作一综述。     

Rapid assay for plasma soluble E-selectin predicts the development of acute respiratory distress syndrome in patients with systemic inflammatory response syndrome

A newly developed rapid immunoassay method for plasma soluble E-selectin (sES) was examined to determine whether it can predict the development of acute respiratory distress syndrome (ARDS) in critically ill patients with systemic inflammatory response syndrome (SIRS). Plasma levels of sES were measured on admission (day 1) to the emergency unit. Development of various types of organ failures including ARDS was compared in the first 5 days of admission (from day 1 to day 5) between patients with normal plasma levels of sES and those with elevated plasma levels of sES. Plasma levels of sES were determined using a newly developed latex agglutination method that takes 20 min to obtain the test results. The normal range of the plasma sES level was 4.8-29.7 ng/mL with this method. Among the patients examined, 22 patients showed elevated sES levels (D(A)E group) and 28 showed normal sES levels (D(A)N group). Development of ARDS was significantly higher in the D(A)E group (15/22, 68.2%) than in the D(A)N group (4/28, 14.3%) (P < 0.001) and that of cardiovascular system failure, renal failure, and coagulation system failure was also significantly higher in the D(A)E group than in the D(A)N group. The mortality rate at 28 days after admission was higher in the D(A)E group (27.3%) than in the D(A)N group (0%) (P < 0.05). Determination of sES levels by this new rapid assay method might be useful for prediction of the development of ARDS in critically ill patients with SIRS, a pathologic condition that has the potential risk for development of multiple organ failure.